What causes transient elevations of conjugated bilirubin (bilirubin)

From the Guidelines

Transient elevations in conjugated bilirubin are most commonly caused by acute viral hepatitis, drug-induced liver injury, alcoholic hepatitis, and biliary obstruction, as supported by the most recent evidence from 1. The causes of transient elevations in conjugated bilirubin can be multifactorial, including:

• Medications such as antibiotics (amoxicillin-clavulanate, macrolides), antiepileptics (phenytoin, carbamazepine), NSAIDs, and certain herbal supplements
• Sepsis, total parenteral nutrition, post-surgical states, and autoimmune conditions like primary sclerosing cholangitis
• Impairment in the liver's ability to excrete conjugated bilirubin into the bile, or obstruction preventing bile flow into the intestine, as explained in 1 These elevations occur when the liver's ability to conjugate bilirubin is disrupted, causing conjugated bilirubin to back up into the bloodstream. Most transient elevations resolve within days to weeks once the underlying cause is addressed, though monitoring liver function tests is important to ensure resolution, as recommended in 1. If a medication is suspected, discontinuation often leads to normalization of bilirubin levels within 2-4 weeks. It is essential to evaluate for alternative etiologies for liver injury, including serologies for hepatotrophic and non-hepatotrophic viruses, and an evaluation of the hepatobiliary tree and hepatic vasculature with abdominal ultrasound, as suggested in 1. In patients with grade 2 hepatitis or higher, liver biopsy should be considered to maximize the diagnostic utility of the biopsy. Current treatment guidelines for ICI hepatitis are based largely on expert opinion and small case series, emphasizing the need for individualized management and close monitoring of liver function tests.

From the FDA Drug Label

Hepatotoxicity including transient abnormalities in liver function tests (e.g., elevations in serum bilirubin, alkaline phosphatase, serum transaminases, gamma-glutamyl transferase), hepatitis, a shock-like syndrome with hepatic involvement and abnormal liver function tests, and cholestasis have been reported Transient increases in liver enzymes and/or bilirubin may occur

The cause of transient elevations of conjugated bilirubin is likely due to hepatotoxicity associated with rifampicin use, which can lead to elevations in serum bilirubin and other liver function tests. This can occur as a result of the drug's effect on the liver, particularly in patients with prior hepatic impairment. Additionally, cholestasis has also been reported, which can contribute to elevated bilirubin levels 2, 2.

From the Research

Causes of Transient Elevations of Conjugated Bilirubin

• Transient elevations of conjugated bilirubin can be caused by various factors, including:
  • Drug-induced hepatitis, which can lead to elevated liver enzymes and bilirubin 3
  • Intrahepatic disorders, such as alcohol, infectious hepatitis, drug reactions, and autoimmune disorders, which can cause conjugated hyperbilirubinemia 4
  • Posthepatic disorders, such as gallstone formation, biliary tract infection, pancreatitis, and malignancies, which can also cause conjugated hyperbilirubinemia 4
  • Inherited disorders of bilirubin clearance, such as Dubin-Johnson syndrome and Rotor syndrome, which can lead to conjugated hyperbilirubinemia 5, 6
• Other potential causes of jaundice and hyperbilirubinemia include:
  • Hemolysis and hematoma resorption, which can lead to elevated levels of unconjugated bilirubin 4
  • Alcoholic liver disease, biliary strictures, choledocholithiasis, drug-induced liver injury, hemolysis, or hepatitis, which can cause jaundice and hyperbilirubinemia 7

Evaluation and Diagnosis

• A comprehensive medical history, review of systems, and physical examination are essential for differentiating potential causes of jaundice and hyperbilirubinemia 7
• Initial laboratory evaluation should include assays for bilirubin (total and fractionated), a complete blood cell count, aspartate transaminase, alanine transaminase, gamma-glutamyltransferase, alkaline phosphatase, albumin, prothrombin time, and international normalized ratio 7
• Imaging studies, such as ultrasonography of the abdomen, computed tomography with intravenous contrast media, and magnetic resonance cholangiopancreatography, may be necessary to evaluate the underlying cause of jaundice and hyperbilirubinemia 7